Chemokines are chemotactic cytokines that are released by a variety of cell types to attract and activate other cell types such as macrophages, T and B lymphocytes, basophils, neutrophils, mast cells, and eosinophils. They are broadly classified as C, CC, CXC, or CX3C chemokines dependent upon their amino acid sequence. For example, in CC chemokines the first two cysteines in the sequence are adjacent, while in CXC chemokines these cysteines are separated by one or more amino acid residues.
Chemokines bind to specific cell-surface receptors that belong to the family of G protein coupled seven transmembrane domain proteins. Upon ligand binding, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in calcium flux, changes in cell morphology, upregulated expression of cellular adhesion molecules, degranulation, and promotion of cell migration.
Chemokine receptors are implicated as key mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma, COPD, and allergic diseases; rheumatoid arthritis, atherosclerosis, and psoriasis; solid organ transplant rejection, osteoarthritis, and inflammatory bowel syndrome. To illustrate, the CCR3 receptor appears to be a key mediator in attracting eosinophils and Th2 polarized CD4+ T cells to sites of inflammation in the lung, and also plays an important role in activating these cells. The ligands that bind CCR3 can induce a rapid increase in the intracellular calcium ion concentration (calcium flux), degranulation, increased expression of cell adhesion molecules, and cell migration. Agents that could modulate activity of the CCR13 receptor would have utility in the treatment of disorders and diseases in which eosinophils or Th2 CD4+ T cells appear to play a prominent role. A similar utility has been demonstrated using antibodies specific for the murine CCR3 chemokine receptor. Such antibodies can be used to deplete eosinophils in in vivo inflammatory models in mice.
Several mammalian viruses such as, but not limited to, cytomegaloviruses, herpesviruses, and poxviruses have been shown to express proteins with the binding properties of chemokine receptors in infected cells. In addition, several chemokine receptors have been demonstrated to act as cellular receptors for a variety of viruses, as well as some bacteria, and parasites. Thus, agents which modulate chemokine receptor activity may also have utility in infectious diseases. Examples would include, but not be limited to, blocking of HIV infection of CCR3, CCR5, or CXCR4 expressing cells; or in the prevention of manipulation of the immune response by viruses such as cytomegaloviruses that use a chemokine receptor for cellular infection.
CCR4 is a chemokine receptor that partners with the ligands MDC (macrophage derived chemokine) and TARC (thymus and activation-regulated chemokine), both of which are members of the beta or CC class of chemokines. The CCR4 chemokine receptor is important in facilitating the migration of selected CD4+ thymocytes to the thymus, and through the compartments of the thymus, as a part of the process of T cell education and differentiation. A CCR4 antagonist is expected to prevent recruitment of CD4+ Th2 polarized T cells to sites of inflammation by blocking chemotaxis and cellular activation. No known CCR4 specific antagonists are in the clinic at this time.
In vivo studies have demonstrated the potential of CCR4 as a therapeutic target. Treatment with antibodies specific for either TARC or MDC is effective in blocking allergic airway inflammation and hyperresponsiveness in mice. Antibodies to TARC are also effective in a bacteria-induced fulminant hepatic liver failure model in mice; a result thought to be due to a reduction in liver injury as mediated by T cells recruited by granuloma-derived TARC. Splenocytes and thymocytes isolated from CCR4−/− mice are unable to migrate in response to TARC or MDC. CCR4−/− mice exhibit significantly decreased mortality on administration of bacterial lipopolysaccharide. Blocking antibody to CCR4 is efficacious in reducing LPS toxicity in mice. Blocking antibody was also efficacious in reducing skin homing of CD4+ Th2 T cells.
CCR4 antagonists are expected to have therapeutic potential in the treatment of diseases such as asthma, rheumatoid arthritis, and psoriasis. Asthma is a chronic inflammatory disease of the airways with an estimated prevalence of 48 million patients in the US, Europe, and Japan. Children and juveniles represent 30% of these patients. Current therapies provide both acute relief of signs and symptoms (beta agonists, xanthines) and chronic disease maintenance (inhaled steroids, leukotriene antagonists). Many of these therapies are inhaled and have significant systemic side effect issues (particularly steroids). Leukotriene antagonists are dosed orally and have a better safety/tolerability profile, but with reduced efficacy compared to steroids. There is a significant need for better oral non-steroidal anti-inflammatory therapies to treat asthma.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease and treatment for RA is aimed at relieving symptoms (analgesics, NSAIDS, steroids) and delaying disease progression (DMARDs). The rapid growth in this market has come from the introduction of new disease modifying agents, primarily biologics, which have improved efficacy and a unique adverse event profile. Although broader ranges of therapeutic options are now available, they are still insufficient to achieve optimal clinical control and there is a significant need for effective and well-tolerated oral medicines for routine maintenance therapy.
Psoriasis is a chronic skin disease and current therapies for psoriasis consist of topicals, UV therapy and potent systemics. Topicals are difficult to use and are not highly efficacious for moderate-to-severe disease. Moderate-to-severe patients (44%) are generally treated with uv therapy and/or systemics. UV therapy is inconvenient and carries the potential risk of skin cancer. Systemics such as cyclosporin or methotrexate come with significant side effects, including kidney and liver toxicity. Biologics are emerging therapies with varying degrees of efficacy. They are well tolerated and safer than current systemics, but require infusion or injection. A significant unmet need exists for a more effective and better-tolerated orally active medicine, particularly with the potential for use in maintenance therapy to prevent flares. An ideal therapy could be used for both clearance and maintenance.
The WO 02/30357 and 02/30358 patent application describes compounds and methods for modulating CCR4 function.
U.S. Pat. No. 6,245,332 is directed to methods for manipulating adhesion triggering and CCR4 mediated chemotaxis to affect the localization of T cells in targeted tissues. In one embodiment of the invention, the active agent is a CCR4 antagonist, that acts to enhance T cell localization. In another embodiment, the agent is an antagonist that blocks cCR4 biological activity.
The WO 98/27815 patent application is directed to aminoquinolines which are useful as modulators ochemokine receptor activity. In particular, the compounds of the invention are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 and/or CXCR-4.
The WO 98/25605 patent application is directed to spiro-substituted azacycles which are useful as modulators of chemokine receptor activity. In particular, the compounds of the invention are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3 and/or CXCR-4.
The WO 99/37617 patent application is directed to a method of treating a subject with a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to the subject a therapeutically effective amount of a compound of the invention.
The WO 01/79209 patent application relates to diazafluorenone derivatives which are IL-8 receptor antagonists and to methods of treating a chemokine-mediated disease in a mammal, including a human. According to this application, chemokine-mediated disease include psoriasis, atopic dermatitis, disease associated with pathological angiogenesis (i.e., cancer), asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative dolitis, gastric ulcer, spetic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, atherosclerosis, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, Alzheimer's disease, graft versus host reaction or allograft rejections in a mammal, including a human.
There remains a need for potent selective antagonists of CCR4 chemokine receptors with improved pharmacological properties, physical properties and fewer side effects. Such inhibitors would have therapeutic potential in the treatment of asthma, rheumatoid arthritis and psoriasis. The compounds of the present invention are effective antagonists of the CCR4 chemokine receptor.